Electroporation is a promising technique for the treatment of inoperable solid tumors either through enhancement of chemotherapy uptake using reversible electroporation, (RE) or through cell death using irreversible electroporation (IRE).
Electroporation involves application of external electric fields to tissue, increasing the voltage drop across cell membranes. This process is not instantaneous and typically takes 1-5 microseconds for the membrane potential to increase from baseline to a steady state maximum. When this potential reaches a critical potential (approximately 0.5-1 V) the molecules in the cell membrane deform in an attempt to minimize the energy in the system. This results in the formation of nanoscale defects (electro-pores) which are either transient and do not affect cell viability (reversible electroporation), or permanent and result in cell death (irreversible electroporation).
Reversible and irreversible electroporation are both useful tools in biology, cancer therapy, and other clinical applications. Conventional commercialized methods for implementing clinical reversible electroporation for electrochemotherapy and electrogenetherapy include the Cliniporator. Conventional commercialized techniques for implementing clinical irreversible electroporation include the NanoKnife.
However, reversible and irreversible electroporation effects typically have uncontrolled overlap, resulting in undesired side-effects. A major unsolved challenge is controlling the extent/ratio to which these effects occur.
For example, reversible electroporation is useful for enhancing drug delivery and gene uptake in vivo. In this process, electrical pulses are used to create temporary defects in cell membranes which enable the uptake of macromolecules. Under certain circumstances, these electrical pulses result in irreversible (IRE) damage to the cells resulting in a focal ablation zone within the tissue. In electro-chemotherapy and electro-gene therapy, significant volumes of tissue may be irreversibly damaged when the clinical intent is to maximize molecular uptake and minimize cell death.
In contrast, when irreversible tissue ablation is desired, the clinical effect is typically limited to an internal volume of complete cell killing surrounded by a region of reversibly electroporated tissue. Irreversible electroporation uses high intensity electrical pulses to focally ablate solid tumors. Clinically, two or more needle electrodes are advanced around a target tumor. A series of approximately 100 electrical positive polarity pulses 1000 to 3000 V in amplitude and 50 to 100 μs in duration are then delivered to disrupt the membranes of cells within a well-defined volume. FIG. 1A shows a pulse waveform for IRE treatments, using a series of long duration positive polarity pulses. These electrical pulses increase cell transmembrane potentials (TMP) above a critical threshold and create permanent nanoscale defects which result in rapid cell death. IRE ablations exhibit a characteristic sub-millimeter translation from complete cell killing to unaffected tissue due to the exponential decrease in electric field intensity in tissue far from the electrodes.
Though IRE is a promising emerging procedure, there are some clinical challenges which may slow widespread adoption of the therapy. The long duration electrical pulses create local and systemic muscle contractions and may inadvertently interact with cardiac rhythms. To alleviate this, patients must receive significant doses of chemical paralysis and pulse delivery is synchronized with the heart beat to ensure pulses are delivered during the absolute refractory period. Additionally, the ablation zone produced by IRE is dependent on local dynamic electrical properties of the tissue and heterogeneities can potentially distort the electric field and produce irregular shaped ablations.
High frequency irreversible electroporation (H-FIRE) is a new protocol which replaces the long duration monopolar IRE pulses with a burst of alternating polarity pulses between 250 ns and 5 μs to alleviate muscle contractions caused by longer duration pulses and produce more predictable ablations. FIG. 1B show a pulse waveform for H-FIRE treatments, using multiple bursts containing 0.25 to 5 μs alternating polarity pulses.
However, previous reports indicate that H-FIRE produces smaller ablations than IRE; reversible electroporation using HF waveforms has yet to be reported clinically.